Lectin-gated and glycan functionalized mesoporous silica nanocontainers for targeting cancer cells overexpressing Lewis X antigen

[EN] Gated mesoporous silica nanoparticles can deliver payload upon the application of a predefined stimulus, and therefore are promising drug delivery systems. Despite their important role, relatively low emphasis has been placed on the design of gating systems that actively target carbohydrate tumor cell membrane receptors. We describe herein a new Lewis X (Le(x)) antigen-targeted delivery system comprising mesoporous silica nanoparticles (MSNs) loaded with ATTO 430LS dye, functionalized with a Le(x) derivative (1) and capped with a fucose-specific carbohydrate-binding protein (Aleuria aurantia lectin (AAL)). This design takes advantage of the affinity of AAL for Le(x) overexpressed receptors in certain cancer cells. In the proximity of the cells, AAL is detached from MSNs to bind Le(x), and selectins in the cells bind Le(x) in the gated MSNs, thereby inducing cargo delivery. Gated MSNs are nontoxic to colon cancer DLD-1 cells, and ATTO 430LS dye delivered correlated with the amount of Le(x) antigen overexpressed at the DLD-1 cell surface. This is one of the few examples of MSNs using biologically relevant glycans for both capping (via interaction with AAL) and targeting (via interaction with overexpressed Le(x) at the cell membrane).The authors thank the Spanish Government (Projects MAT2015-64139-C4-1-R and MAT2013-46101-R (MINECO/ FEDER)), Fondo de Investigacion Sanitaria (PI15/00480) and Generalitat Valenciana (Project PROMETEOII/2014/047 and project GVA/2014/13) for support. R. B. is thankful to Svagata. Eu (Erasmus Mundus Action-II program) for his fellowship. The authors also thank the Electron Microscopy Service at the UPV for support.Bhat, R.; García, I.; Aznar, E.; Arnáiz, B.; Martínez-Bisbal, M.; Liz-Marzán, L.; Penadés, S.... (2018). 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4-(4,5-Diphenyl-1H-imidazole-2-yl)-N,N-dimethylaniline-Cu(II) complex, a highly selective probe for glutathione sensing in water-acetonitrile mixtures

The imidazole derivative 4-(4,5-diphenyl-1H-imidazol-2-yl)-N,N-dimethylaniline (probe 1) formed a highly coloured and non-emissive 1:1 stoichiometry complex with Cu(II) in water-acetonitrile 1:1 (v/v) solutions. Among all the amino acids (Lys, Val, Gln, Leu, His, Thr, Trp, Gly, Phe, Arg, Ile, Met, Ser, Ala, Pro, Tyr, Gly, Asn, Asp, Glu, Cys and Hcy) and tripeptides (GSH) tested, only GSH induced the bleaching of the 1·Cu(II) solution together with a marked emission enhancement at 411 nm (excitation at 320 nm). These chromo-fluorogenic changes were ascribed to a selective GSH-induced demetallation of the 1·Cu(II) complex that resulted in a recovery of the spectroscopic features of probe 1. In addition to the remarkable selectivity of 1·Cu(II) complex toward GSH a competitive limit of detection as low as 2 μM was determined using fluorescence measurements.We thank the Spanish Government (MAT2015-64139-C4-1-R) and Generalitat Valenciana (PROMETEOII/2014/047). H. E. O. thanks Generalitat Valenciana for his Grisolia fellowship. Thanks are also due to Fundação para a Ciência e Tecnologia (Portugal) for financial support to the Portuguese NMR network (PTNMR, Bruker Avance III 400-Univ. Minho), FCT and FEDEReCOMPETEQREN-EU for financial support to the research centre CQUM (UID/QUI/0686/2016) and a doctoral grant to R.C.M. Ferreira (SFRH/BD/86408/2012). The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project No 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC).info:eu-repo/semantics/publishedVersio

Enzyme-Powered Gated Mesoporous Silica Nanomotors for On-Command Intracellular Payload Delivery

[EN] The introduction of stimuli-responsive cargo release capabilities on self-propelled micro- and nano- motors holds enormous potential in a number of applications in the biomedical field. Herein, we report the preparation of mesoporous silica nano-particles gated with pH-responsive supramolecular nanovalves and equipped with urease enzymes which act as chemical engines to power the nanomotors. The nanoparticles are loaded with different cargo molecules ([Ru(bpy)(3)]Cl-2 (bpy = 2,2'-bipyridine) or doxorubicin), grafted with benzimidazole groups on the outer surface, and capped by the formation of inclusion complexes between benzimidazole and cyclodextrin-modified urease. The nanomotor exhibits enhanced Brownian motion in the presence of urea. Moreover, no cargo is released at neutral pH, even in the presence of the biofuel urea, due to the blockage of the pores by the bulky benzimidazole:cyclodextrin-urease caps. Cargo delivery is only triggered on-command at acidic pH due to the protonation of benzimidazole groups, the dethreading of the supramolecular nanovalves, and the subsequent uncapping of the nanoparticles. Studies with HeLa cells indicate that the presence of biofuel urea enhances nanoparticle internalization and both [Ru(bpy)(3)]Cl-2 or doxorubicin intracellular release due to the acidity of lysosomal compartments. Gated enzyme-powered nanomotors shown here display some of the requirements for ideal drug delivery carriers such as the capacity to self-propel and the ability to "sense" the environment and deliver the payload on demand in response to predefined stimuli.A.L.-L. is grateful to La Caixa Banking Foundation for his Ph.D. grant. A.G.-F. thanks the Spanish government for her FPU fellowship. The authors are grateful to the Spanish Government (MINECO Projects MAT2015-64139-C4-1, CTQ2014-58989- PCTQ2015-71936-REDT, CTQ2015-68879-R (MICRODIA) and CTQ2015-72471-EXP (Enzwim)), the BBVA foundation (MEDIROBOTS), the CERCA Programme by the Generalitat de Catalunya, and the Generalitat Valenciana (Project PROMETEO/2018/024 and PROMETEOII/2014/061) for support. T.P. thanks MINECO for the Juan de la Cierva postdoctoral fellowship and the European Union's Horizon 2020 research and innovation program, under the Marie Sk¿odowska-Curie Individual Fellowship (H2020-MSCA-IF2018, DNA-bots). A.C.H. thanks MINECO for the Severo Ochoa fellowship. The authors would like to thank A. Miguel Lopez for the development of the python code for motion analysis.Llopis-Lorente, A.; García-Fernández, A.; Murillo-Cremaes, N.; Hortelao, A.; Patiño, T.; Villalonga, R.; Sancenón Galarza, F.... (2019). Enzyme-Powered Gated Mesoporous Silica Nanomotors for On-Command Intracellular Payload Delivery. ACS Nano. 13(10):12171-12183. https://doi.org/10.1021/acsnano.9b067061217112183131

Toxicological assessment of mesoporous silica particles in the nematode Caenorhabditis elegans

[EN] Here we report the toxicological evaluation of mesoporous silica particles (MSPs) in the nematode C. elegans. Specifically, we have investigated the effect of bare micro- (M0) and nano-sized (N0) MSPs, and their corresponding functionalized particles with a starch derivative (Glu-N) (M1 and N1, respectively) on C. elegans ageing parameters. The toxicity of MSPs, their impact on C. elegans lifespan, movement capacity, progeny and ability to survive upon exposure to acute oxidative stress were assessed. This study demonstrated that both size particles assayed (M0 and N0), labeled with rhodamine and monitored through fluorescence microscopy, are ingested by the nematode. Moreover, toxicity assays indicated that bare nano-sized particles (N0) have a negative impact on the C. elegans lifespan, reducing mobility and progeny production. By contrast, micro-sized particles (M0) proved innocuous for the nematodes. Furthermore, functionalization of nanoparticles with starch derivative reduced their toxicity in C. elegans. Thus, oral intake of N1 comparatively increased the mean lifespan and activity rates as well as resistance to oxidative stress. The overall findings presented here demonstrate the influence of MSP size and surface on their potential toxicity in vivo and indicate the silica-based mesoporous particles to be a potential support for encapsulation in oral delivery applications. Furthermore, the good correlation obtained between healthy aging variables and viability (mean lifespan) validates the use of C. elegans as a multicellular organism for nanotoxicology studies of MSPs.The authors wish to express their gratitude to the Spanish Government (MINECO Projects AGL2012-39597-C02-01, AGL2012-39597-C02-02, AGL2015-70235-C2-1, MAT2012-38429-C04-01 and MAT2015-64139-C4-1), the Generalitat Valenciana (Project PROMETEOII/2014/047) and Colombian Administrative Department of Science, Technology and Research which supported Ms. Acosta Scholarship. We would also like to thank the Institut de Ciencia dels Materials (ICMUV), the Microscopy Service of the Universitat Politecnica de Valencia and the microscopy service of IATA for technical support. We thank Roquette for the Glucidex samples.Acosta-Romero, C.; Barat Baviera, JM.; Martínez-Máñez, R.; Sancenón Galarza, F.; Llopis Llopis, S.; Gonzalez, N.; Genovés, S.... (2018). Toxicological assessment of mesoporous silica particles in the nematode Caenorhabditis elegans. Environmental Research. 166:61-70. https://doi.org/10.1016/j.envres.2018.05.018S617016

Evaluation Activities in Pharmacognosy

La implantación del EEES comporta un nuevo sistema educativo enfocado al aprendizaje basado en el trabajo del estudiante, el cual deja de ser un sujeto pasivo que adquiere y memoriza conocimientos para convertirse en un sujeto activo de su desarrollo competencial y ser capaz de gestionar sus conocimientos eficientemente, bajo la tutela del profesor. Esto implica modificar no sólo la docencia sino también la evaluación, que como parte esencial del proceso educativo, asegura cubrir necesidades de aprendizaje y actualizar contenidos, proporciona retroalimentación, reflexión y análisis de la propia práctica y permite corregir deficiencias y mejorar metodologías. En Farmacognosia, actualmente en segundo curso de la Licenciatura de Farmacia, se han introducido estrategias de evaluación coherentes con los resultados de aprendizaje descritos, a considerar cuando se inicie el desarrollo de sus competencias en tercer curso de Grado. Inicialmente, se ha realizado una prueba de conocimientos previos. Se han aplicado dos tipos de pruebas, unas que enfatizan en la adquisición y comprensión de conocimientos y otras que abarcan competencias disciplinarias y transversales. Entre las primeras se han incluido: tests en aula virtual, que permiten discriminar información y dar una retroalimentación rápida; pruebas de respuesta abierta para comprobar capacidad de expresión, organización de ideas y razonamiento; y resolución de problemas para ver capacidad de gestionar información. Entre las segundas, después de realizar prácticas de laboratorio, se plantea una prueba de ejecución para una droga problema y se elabora un informe que demuestre el desarrollo de la ejecución, búsqueda y selección de información, observación e interpretación de resultados, y posterior exposición oral para valorar capacidad de comunicación.The implantation of the European Higher Education Area (EHEA) requires an educational system rooted in a competency-based learning approach in which, under professorial supervision, the students become active agents in order to reach a sufficient level of competence, retain more knowledge, and manage and apply this knowledge more efficiently. It implies modifying not only our teaching practices, but also our methods of evaluation, which, as an essential part of the education process, guarantees the acquisition of an ample range of skills and keeps course material up to date while providing students and educators with feed-back, reflection and analysis of the whole process. This, in turn, facilitates the correction of deficiencies and improvement of methodologies. In Pharmacognosy, which is currently taught in the second year of the Pharmacy program and in which ca. 200 students are enrolled, various evaluation strategies coherent with the established learning objectives were introduced to two groups of students. We first administered a questionnaire to ascertain the range of knowledge the students already had in related subjects. Then, two types of test were given: one type emphasizing the acquisition and understanding of knowledge and the other type focussing on more generic, interdisciplinary competence. The former type included: on-line multiple choice questionnaires, which allow for discernment of information and quick feed-back; open answer tests to determine the students’ ability to reason, organize their thoughts and express their ideas; and the resolution of problems to see how the students handle information. The latter type of exercise was given to pairs of students who, upon completing the laboratory component of the class, were given a proposal for solving a problem relating to a crude drug. The students then had to draft a scientific paper-like document describing the experimental protocol along with their observations, analysis of the results, and how they searched for and selected information. Finally, the students gave an oral presentation of the protocol and their findings, thus allowing the professor to evaluate their oral communication skills.Este trabajo ha sido financiado con un proyecto de innovación educativa, modalidad Finestra Oberta (29/FO/8) del Vicerectorat de Convergència Europea i Qualitat de la Universitat de València

Glucose-Responsive Enzyme-Controlled Mesoporous Nanomachine with a Layer-by-Layer Supramolecular Architecture

American Chemical Society[EN] Here we describe the construction of an integrated and pH-sensitive nanomachine with layer-by-layer supramolecular design and enzymatic control for on-command delivery. The nanodevice comprises a first layer of ß-cyclodextrin-coated gold nanoparticles as capping element of benzimidazole functionalized mesoporous silica nanoparticles, and a second control layer based on an adatamantane-modified glucose oxidase derivative. The nanomachine was selectively fuelled by glucose and successfully employed for the autonomous release of doxorubicin in HeLa cancer cells.Financial support from the Spanish Ministry of Economy and Competitiveness (projects CTQ2014-58989-P, CTQ2015-71936-REDT, CTQ2017-87954-P, and MAT2015-64139-C4-1-R) and generalitat Valenciana (project PROMETEO/2018/024) is gratefully acknowledged.Jimenez-Falcao, S.; De Luis-Fernández, B.; García-Fernández, A.; Llopis-Lorente, A.; Diez-Sánchez, P.; Sánchez, A.; Sancenón Galarza, F.... (2019). Glucose-Responsive Enzyme-Controlled Mesoporous Nanomachine with a Layer-by-Layer Supramolecular Architecture. ACS Applied Bio Materials. 2(8):3321-3328. https://doi.org/10.1021/acsabm.9b00338S332133282

Nonordered dendritic mesoporous silica nanoparticles as promising platforms for advanced methods of diagnosis and therapies

Dendritic mesoporous silica nanoparticles (DMSNs) are a new generation of porous materials that have gained great attention compared to other mesoporous silicas due to attractive properties, including straightforward synthesis methods, modular surface chemistry, high surface area, tunable pore size, chemical inertness, particle size distribution, excellent biocompatibility, biodegradability, and high pore volume compared with conventional mesoporous materials. The last years have witnessed a blooming growth of the extensive utilization of DMSNs as an efficient platform in a broad spectrum of biomedical and industrial applications, such as catalysis, energy harvesting, biosensing, drug/gene delivery, imaging, theranostics, and tissue engineering. DMSNs are considered great candidates for nanomedicine applications due to their ease of surface functionalization for targeted and controlled therapeutic delivery, high therapeutic loading capacity, minimizing adverse effects, and enhancing biocompatibility. In this review, we will extensively detail state-of-the-art studies on recent advances in synthesis methods, structure, properties, and applications of DMSNs in the biomedical field with an emphasis on the different delivery routes, cargos, and targeting approaches and a wide range of therapeutic, diagnostic, tissue engineering, vaccination applications and challenges and future implications of DMSNs as cuttingedge technology in medicine

A Phase I/II Clinical Trial to evaluate the efficacy of baricitinib to prevent respiratory insufficiency progression in onco-hematological patients affected with COVID19: a structured summary of a study protocol for a randomised controlled trial

Objectives: Baricitinib is supposed to have a double effect on SARS-CoV2 infection. Firstly, it reduces the inflammatory response through the inhibition of the Januse-Kinase signalling transducer and activator of transcription (JAK-STAT) pathway. Moreover, it reduces the receptor mediated viral endocytosis by AP2-associated protein kinase 1 (AAK1) inhibition. We propose the use of baricinitib to prevent the progression of the respiratory insufficiency in SARS-CoV2 pneumonia in onco-haematological patients. In this phase Ib/II study, the primary objective in the safety cohort is to describe the incidence of severe adverse events associated with baricitinib administration. The primary objective of the randomized phase (baricitinib cohort versus standard of care cohort) is to evaluate the number of patients who did not require mechanical oxygen support since start of therapy until day +14 or discharge (whichever it comes first). The secondary objectives of the study (only randomized phase of the study) are represented by the comparison between the two arms of the study in terms of mortality and toxicity at day+30. Moreover, a description of the immunological related changes between the two arms of the study will be reported. Trial design: The trial is a phase I/II study with a safety run-in cohort (phase 1) followed by an open label phase II randomized controlled trial with an experimental arm compared to a standard of care arm

Alien Planktonic Species in the Marine Realm: What Do They Mean for Ecosystem Services Provision?

Human well-being is significantly affected by the contributions provided by ecosystems, or ecosystem services. In this well-illustrated atlas, world-class experts identify and discuss key driving forces, trade-offs, and synergies of ecosystem services. Through interdisciplinary case studies varying across ecosystems and scales, this atlas narrows the knowledge gap between ecosystem services management and related fields of study. This atlas begins with conceptual background and proceeds to present drivers and their risks for ecosystems, their functions and services, and biodiversity. Trade-offs and synergies among ecosystem services and societal responses to the drivers and trade-offs are discussed. Sustainable land management and governance concepts are demonstrated throughout the atlas. Environmental scientists, practitioners and policy makers worldwide will appreciate the solutions and best practices identified throughout the chapters. Students of environmental sciences, socio-economics and landscape planning will find this atlas to be a valuable read, as well

Nonordered dendritic mesoporous silica nanoparticles as promising platforms for advanced methods of diagnosis and therapies

Dendritic mesoporous silica nanoparticles (DMSNs) are a new generation of porous materials that have gained great attention compared to other mesoporous silicas due to attractive properties, including straightforward synthesis methods, modular surface chemistry, high surface area, tunable pore size, chemical inertness, particle size distribution, excellent biocompatibility, biodegradability, and high pore volume compared with conventional mesoporous materials. The last years have witnessed a blooming growth of the extensive utilization of DMSNs as an efficient platform in a broad spectrum of biomedical and industrial applications, such as catalysis, energy harvesting, biosensing, drug/gene delivery, imaging, theranostics, and tissue engineering. DMSNs are considered great candidates for nanomedicine applications due to their ease of surface functionalization for targeted and controlled therapeutic delivery, high therapeutic loading capacity, minimizing adverse effects, and enhancing biocompatibility. In this review, we will extensively detail state-of-the-art studies on recent advances in synthesis methods, structure, properties, and applications of DMSNs in the biomedical field with an emphasis on the different delivery routes, cargos, and targeting approaches and a wide range of therapeutic, diagnostic, tissue engineering, vaccination applications and challenges and future implications of DMSNs as cutting-edge technology in medicine